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Background  Transient receptor potential cation channel subfamily M member 8 (TRPM8) is activated by cold temperature  in vitro  and has been demonstrated to act as a ‘cold temperature sensor’  in vivo . Although it is known that agonists of this ‘cold temperature sensor’, such as menthol and icilin, cause a transient increase in body temperature (T b ), it is not known if TRPM8 plays a role in T b  regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in T b  regulation.    Results  We characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496) as potent and selective antagonists of TRPM8 and tested their effects on T b  in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in T b  (maximum decrease of 0.98°C). Since thermoregulation is a homeostatic process that maintains T b  about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in T b . Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the T b  decrease Day 2 onwards.    Conclusions  The data reported here demonstrate that TRPM8 channels play a role in T b  regulation. Further, a reduction of magnitude in T b  decrease after repeated dosing of an antagonist suggests that TRPM8’s role in T b  maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics.

Transient Receptor Potential Melastatin 8 (TRPM8) Channels are Involved in Body Temperature Regulation